Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges

Alessandro Leonetti, Francesco Facchinetti, Roberta Minari, Alessio Cortellini, Christian D. Rolfo, Elisa Giovannetti, Marcello Tiseo

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

Background: Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients’ prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85% of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. Conclusions: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.
LanguageEnglish
JournalCellular Oncology
DOIs
Publication statusPublished - 2019

Cite this

Leonetti, Alessandro ; Facchinetti, Francesco ; Minari, Roberta ; Cortellini, Alessio ; Rolfo, Christian D. ; Giovannetti, Elisa ; Tiseo, Marcello. / Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges. In: Cellular Oncology. 2019.
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title = "Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges",
abstract = "Background: Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients’ prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85{\%} of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. Conclusions: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.",
author = "Alessandro Leonetti and Francesco Facchinetti and Roberta Minari and Alessio Cortellini and Rolfo, {Christian D.} and Elisa Giovannetti and Marcello Tiseo",
year = "2019",
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Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges. / Leonetti, Alessandro; Facchinetti, Francesco; Minari, Roberta; Cortellini, Alessio; Rolfo, Christian D.; Giovannetti, Elisa; Tiseo, Marcello.

In: Cellular Oncology, 2019.

Research output: Contribution to journalReview articleAcademicpeer-review

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T1 - Notch pathway in small-cell lung cancer: from preclinical evidence to therapeutic challenges

AU - Leonetti, Alessandro

AU - Facchinetti, Francesco

AU - Minari, Roberta

AU - Cortellini, Alessio

AU - Rolfo, Christian D.

AU - Giovannetti, Elisa

AU - Tiseo, Marcello

PY - 2019

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N2 - Background: Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients’ prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85% of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. Conclusions: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.

AB - Background: Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients’ prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85% of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. Conclusions: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.

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